Most solid tumors have a high rate of cell death and contain regions of necrosis. Previous studies have shown that the edge of a necrotic tumor region is oftenparallel to a nearby capillary, suggesting the importance of limited diffusion of metabolites in causing cell death. Although killing tumor cells is a major goal of cancer research, thereis scant information about factors which lead to cell death in untreated tumors. A goal of the present research is to understand the interactions between nutrients and metabolites that lead to cell death in tumors. The influence of nutrient environment on cell viability will be studied using single cells in culture and spheroids. Spheroids consist of aggregates of cells that grow in tissue culture and develop central necrosis. Morphologically, spheroids appear identical to nodules that occur within solid tumors, and they provide a powerful model of intermediate complexity for studying the influence of metabolite diffusion on cell death. Nutritionally-deprived cells in solid tumors and spheroids are probably spared by some anticancer drugs (e.g., adriamycin) because of limited drug distribution from blood vessels or the surrounding medium. Resistance to drugs may result also from the lower proliferative rate of poorly nourished tumor cells, while hypoxia conveys resistance to radiation. Therapeutic index might, therefore, be improved by combining anticancer drugs or radiation with other drugs that are specific for nutritionally-deprived cells. Drugs which might stimulate (or imitate) natural causes of cell death in tumors will be tested against nutritionally-deprived cells in tissue culture and in vivo. Such drugs would not be effective when used alone, and would fail the current NIH screen, but might dramatically improve the results of therapy when used with agents such as radiation or adriamycin. (N)